9{86 ,15{86 -Dihydroxy-11{60 -hydroxymethylprost-13(trans)-enoic acid derivatives

ABSTRACT

Prostenoic acid derivative having the formula   WHEREIN A represents an alkylene group having from 4 to 8 carbon atoms, R1 represents an alkyl group having from 4 to 10 carbon atoms, R2 represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms and R3 represents hydrogen atom or an alkoxycarbonyl group having from 1 to 6 carbon atoms in the alkyl moiety and pharmaceutically acceptable salts thereof. The compounds are useful as oxytocic agents and may be prepared by reducing the compound having the formula   WHEREIN A, R1, R2 and R3 have the meanings given above with a metal hydride complex, for example, sodium boron hydride and potassium boron hydride in the presence or absence of an inert organic solvent.

United States Patent 11 1 Oda et al.

[ 1 Aug. 12, 1975 [54] 9,15-DIHYDROXY-1la-HYDROXYME- THYLPROST- l 3TRANS -ENOIC ACID DERIVATIVES [75] Inventors: Osamu Oda; Kiyoshi Sakai;Takashi Yusa; Hamako Katano, all of Tokyo, Japan [73] Assignee: SankyoCompany Limited, Tokyo,

Japan 22 Filed: Aug. 27, 1973 21 Appl.No.: 392,113

[30] Foreign Application Priority Data Sept. 1, 1972 Japan 47-8817] [52]US. Cl ..260/463; 260/247.2 R, 260/243.65. 260/326.3, 260/343.2 R,260/410.9 R.

260/468 D. 260/476, 260/268 R, 260/295 S. 260/390.9. 260/345.8, 260/413,260/468 R.

[51] Int. Cl... C07C 61/32; CO7C 67/00; CO7C 69/74 [58] Field of Search.260/463. 468. 514

7,311,403 2/1974 Netherlands 260/468 Primary Examiner-Robert GerstlAttorney, Agent, or Firm-Flynn & Frishauf [57] ABSTRACT Prostenoic acidderivative having the formula wherein A represents an alkylene grouphaving from 4 to 8 carbon atoms, R represents an alkyl group having from4 to 10 carbon atoms, R represents hydrogen atom or an alkyl grouphaving from one to 6 carbon atoms and R represents hydrogen atom or analkoxycarbonyl group having from one to 6 carbon atoms in the alkylmoiety and pharmaceutically acceptable salts thereof.

The compounds are useful as oxytocic agents and may be prepared byreducing the compound having the formula 3 R OH C wherein A, R, R and Rhave the meanings given above with a metal hydride complex, for example,sodium boron hydride and potassium boron hydride in the presence orabsence of an inert organic solvent.

6 Claims, N0 Drawings 1 9,15-DIHYDROXY-11a-HYDROXYMETHYL- PROST- l3(TRANS)-ENOIC ACID DERIVATIVES This invention relates to novelprostaglandin derivatives and a novel process for the preparationthereof.

More particulary, it relates to a 9g,l-dihydroxylla-hydroxymethylprost-l3(trans)-enoic acid derivativeshaving the formula atoms, preferably, pentamethylene,lmethylpentamethylene, Z-methylpentamethylene, hexamethylene,l-methylhexamethylene, 2- methylhexamethylene, heptamethylene andlmethylheptamethylene, R may be a straight or branched alkyl grouphaving from 4 to 10 carbon atoms, preferably, n-butyl, isobutyl,n-pentyl, isopentyl, l-methylpentyl, Z-methylpentyl, 1 l-dimethylpentyl, 1,2-dimethylpentyl, n-hexyl, isohexyl, l-methylhexyl,1,1-dimethylhexyl, 1,2-dimethylhexyl, n-heptyl, isoheptyl, n-octyl andisooctyl. R represents hydrogen atom or an alkyl group having from 1 to6 carbon atoms and the alkyl group may be straight or branched,preferably, methyl, ethyl and n-propyl. R represents hydrogen atom or analkoxycarbonyl group having from 1 to 6 carbon atoms, e.g.,ethoxycarbonyl, npropoxycarbonyl and n-butoxycarbonyl.

A preferred group of the prostaglandin derivatives provided by theinvention are those of the formula (I) wherein A representshexamethylene group, i.e., those having the formula wherein R, R and Rare the same as above and the pharmaceutically acceptable salts thereof.

In formulae (1) and (I-a), and elsewhere in this specification, a bondattached to the cyclopentane nucleus which is in the oz-configuration,i.e., extends below the plane of the cyclopentane ring, is representedby a dotted line, and a bond which is in the ,B-configuration, i.e.,extends above the plane of the cyclopentane ring, is represented by asolid line. The wavy line indicates that either steric configuration ispossible.

The pharmaceitucally acceptable salts of the acids of formulae (I) and(I-a) in which R is hydrogen atom include alkali and alkaline earthmetal salts, e.g., the sodium, potassium, magnesium and calcium salts,quaternary ammonium salts, e.g., the ammonium, tetramethylammonium,tetraethylammonium, benzyltrimethylammonium and phenyltriethylammoniumsalts, aliphatic, alicyclic or aromatic amine salts, e.g., themethylamine, ethylamine, dimethylamine, diethylamine, trimethylamine,triethylamine, N-methylhexylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, a-phenylethylamine and ethylene diaminesalts, heterocyclic amine salts, e.g., the piperidine, morpholine,pyrrolidine, piperazine, pyridine, l-methylpiperazine and4-ethylmorpholine salts, salts of amines which are water-soluble orcontain a hydrophilic group, e.g., the monoethanolamine,ethyldiethanolamine and Z-amino-l-butanol salts. Such salts may beprepared from the acids of formulae (I) and (I-a) in which R is hydrogenatom by the conventional techniques.

enoic acid dissolved in isotonic sodium chloride solution containing asmall amount of sodium bicarbonate. Uterine activity was measured byrecording changes in intraamniotic pressure from a balloon introducedinto the amniotic cavity through the cervix.

Accordingly, the compounds of the invention are useful as oxytocicagents; and the invention provides pharmaceuticalcompositions comprisinga compound of formula (I), or a pharmaceutically acceptable saltsthereof, and a pharmaceutical carrier or diluent. The pharmaceuticalcompositions of the invention are generally formulated for parenteraladministration. For example, the compounds of formula (I) may beadministered by continuous intravenous infusion, dissolved in sterile,pyrogen-free isotonic sodium chloride solution. The optimum dosage ofthe compounds of the invention will vary with the body weight and age ofthe patient; but the parenteral total daily dosage for full-termpregnant women will generally be from about 0.5 g. to

According to the present invention, the compound having the formula (I)may be prepared by reducing a compound having the formula wherein A, R Rand R are the same as above with a metal hydride complex in the presenceor absence of an inert organic solvent.

The reduction maybe preferably carried out by contacting the compound(II), (III) or (IV) with the metal hydride complex in the presence of aninert organic solvent. Preferable examples of the metal hydride complexinclude alkali metal boron hydrides, e.g., sodium boron hydride,potassium boron hydride, lithium boron hydride, sodium cyano boronhydride, lithium 9b-boro-perhydrophenalene hydride; alkali metalaluminum hydrides, e.g., aluminum tri-tert.-butoxylithium hydride,aluminum trimethoxylithium hydride; and zinc boron hydride. Preferableexamples of the inert organic solvent include alcohols, e.g., methanoland ethanol; ethers, e.g., diethyl ether, tetrahydrofuran, dioxane,diglyme; and dialkylformamides, e. g., dimethylformamide. The reductionis preferably carried out at relatively low temperatures, usually at atemperature from lOC. to room temperature. The reaction period willdepend mainly upon the reaction temperature and a kind of the reducingagent. It is usually from about 30 minutes to 3 hours.

After completion of the reaction, the desired product may be recoveredfrom the reaction mixture by conventional means. For instance, organicacids, e.g., formic acid and acetic acid, are added to the reactionmixture in order to decompose the excess reducing agent and the mixtureis extracted with an organic solvent. The extract is washed with waterand dried and the solvent is'distilled off to give the desired product.The product thus obtained may be further purified, if necessary, byconventional means, forv example, column chromatography or thin-layerchromatography.

The compounds of the formula (I) and their salts can exist as fourdifferent optical isomers, depending up n the configuration of thehydroxy groups attached to the cyclopentane nucleusand the side-chain.The racemic mixtures of these isomers can be resolved by "16 con.-ventional techniques. so as to obtain the desir ucts in he form ofoptically pure diastereoisomers formulae (I) and (l-a') are used torepresent both diastereoisomeric forms. as well as the racemic mixtures.but the pure isomers are included within the scope of the invention, aswell as their mixtures.

The hydroxyand carboxy-protecting group may be removed by conventionalmeans, for example, by treating the compound (II), (III) or (IV) with anacid, e.g., acetic acid, hydrochloric acid or with a base, e.g., sodiumhydroxide, sodium carbonate.

The compounds of the formulae (II), (III) and (IV), employed as startingmaterials in the preparation of the compounds of the invention. are alsonovel and can be prepared by the processes shown in the followingreaction schemes.

Prepara tinn of the compounds (II) 0' o o o o x, 4 I 4 R ooc U co'oRR40OC COORS R 00c coon (V) (VI) J. Org. Chem. 36,

In the above scheme, A, R, R and R are the same as above, R R R, R R andR may be the same or different and each represents an alkyl group havingfrom 1 to 6 carbon atoms. Each of theabove steps may be illustrated asfollows: i v

The compound (VI) may be prepared by reacting the compound (V) withethylene glycol in the presence of a Lewis acid, e.g., borontrifluoride. The reaction is preferably carried out in an inert organicsolvent such as dichloromethane, chloroform or benzene at a temperatureranging from 0C. to room temperature.

The compound (VII) may be prepared by reacting the compound (VI) with analkali metal compound, e.g., sodium methoxide, potassium ethoxide,sodium hydroxide. The reaction is preferably carried out in an inertorganic solvent such as tetrahydrofuran, dioxane or methanol at atemperature ranging from OC.'to a reflux temperature of the reactionmixture. In this step, the bond of the group COOR is changed fromB-configuration to a-con'figuration.

The compound (VIII) may be prepared by reducing the compound (VII) witha metal hydride compound such as sodium boron hydride, potassium boronhydride, lithium boron hydride, trimethoxylithium aluminum hydride oraluminum, lithium hydride. The reaction is preferably carried out in aninert organic solvent such as methanol, tetrahydrofuran or ether at atemperature ranging from 0C. to a reflux temperature of the reactionmixture.

The compound (IX) or (XVI) may be prepared respectively by reacting thecompound (VIII) or (XV) with a compound having the formula X COOR or XCOOR wherein R and R are the same as above and X and X represent ahalogen atom, e.g., chlorine, bromine, iodine in the presence of a basesuch as sodium carbonate, sodium' bicarbonate, triethylamine, pyridineor N-methylpiperazine. The reaction is preferably carried out below roomtemperature.

The compound (X) may be prepared by reacting the compound (IX) with anacid such as formic acid, acetic acid, hydrochloric acid, hydrobromicacid or sufuric acid. The reaction is preferably carried out in asolvent such as water, methanol, ether or acetone at a temperatureranging from 0C. to 60C.

The compound (XI) may be prepared by reacting the compound (X) with analkali metal compound such as alkali metal alkoxides, e.g., sodiummethoxide, potassium ethoxide, potassium tert.-butoxide; alkali metalhydrides, e.g., sodium hydride, potassium hydride; or alkali metalhydroxides, e.g., sodium hydroxide, potassium hydroxide. The reaction ispreferably carried out in an inert organic solvent such astetrahydrofuran, ether and benzene at a temperature ranging from -50C.to 80C. in an inert gas atmosphere, for example in argon or heliumatmosphere.

The compound (XII) may be prepared by reacting the compound (XI) with acompound having the formula X A COOR wherein A and R are the same asabove and X represents a halogen atom, e.g., bromine, chlorine, in thepresence of an alkali metal compound such as alkali metals, e.g.,metallic sodium; alkali metal hydroxides, e.g., sodium hydroxide,potassium hydroxide; or alkali metal alkoxides, e.g., sodium methoxide,potassium ethoxide.'The reaction is preferably carried out in an inertorganic solvent, e.g., benzene, ether, tetrahydrofuran, dimethylsulfoxide, below room temperature in an inert gas atmosphere, forexample in argon or helium atmosphere.

The compound (XIII) may be prepared by reacting the compound (XII) withan alkali metal compound such as sodium hydroxide, potassium hydroxide,so-

dium carbonate or potassium carbonate. The reaction is preferablycarried out in a solvent, e.g., water, methanol, ether, dioxane, amixture of water and such an organic solvent, at a temperature rangingfrom room temperature to reflux temperature of the reaction mixture inan inert gas atmosphere, for example, in an argon or helium atmosphere.

The compound (XIV) may be prepared by contacting the compound (XIII)with an oxidizing agent such as chromic acid, chromic anhydride, chromicanhydride-pyridine complex, sodium bichromate dimethylsulfoxide-chlorine complex, dimethyl sulfoxide-acetic anhydride. Thereaction is preferably carried out in a solvent such as acetic acid,dichloromethane and chloroform at a temperature ranging from 0C. to roomtemperature.

The compound (XV) may be prepared by contacting the compound (XIV) withan acid such as formic acid, acetic acid, hydrochloric acid or sulfricacid, or with an alkali metal compound such as sodium hydroxide,potassium hydroxide or sodium carbonate. The reaction is preferablycarried out in a solvent, e.g., water, methanol, ether at a temperatureranging from room temperature to reflux temperature of the reactionmixture.

The compound (XVII) may be prepared by reacting the compound (XV) withan alcohol, e.g., diazomethane and diazoethane.

The compound (II) may be prepared by reacting the compound (XIV), (XV),(XVI) or (XVII) with a Wittig reagent having the formula wherein R isthe same as above and R represents an alkyl group having'from l to 6carbon atoms or phenyl group. At least I mole of the Wittig reagent isused per mole of the compound (XIV), (XV), (XVI) or (XVII) andpreferably from 2 to 10 moles of the Wittig agent is used. The reactionis generally carried out in an inert organic solvent such as ether,benzene, toluene, hexane, dimethyl sulfoxide, tetrahydrofuran, methylenechloride or chloroform, at a temperature ranging from O C. to a refluxtemperature of the reaction mixture, preferably at room temperature orbelow and in an inert gas atmosphere, for example, in an argon or heliumatmosphere. The reaction is carried out for a period of Shows to 30hours depending on the temperature and concentration of the reactionmixture and the specific Wittig reagent used.

The product obtained in each step of the above processmay be recoveredfrom the reaction mixture in a conventional manner, for example, byevaporating the solvent from the reaction mixture or by adding water andextracting with a water-immiscible solvent. The crude product can bepurified by conventional means such as recrystallization orchromatography.

Preparation of the compounds (III) In the above scheme, A, R, R R", Rand R are the same as above.

Each of the above steps may be illustrated as follows:

The compound (XVII) may be prepared by reacting the compound (XIII) withethylene glycol in the presence of a Lewis acid, e.g., borontrifluoride. The reaction is preferably carried out in an inert organicsolvent such as dichloromethane, chloroform or benzene at a temperatureranging from 0C. to room temperature.

The compound (XIX) may be prepared by contacting the compound (XVIII)with an oxidizing agent such as chromic acid, chromic anhydride, chromicanhydride-pyridine complex, sodium bichromate, dimethylsulfoxide-chlorine complex, dimethyl sulfoxide-acetic anhydride. Thereaction is preferably carried out in a solvent such as acetic acid,dichloromethane, chloro- 60 perature of the reaction mixture.

The compound (XXI) may be prepared by reacting the compound (XIX) or(XX) with a Wittig reagent having the formula wherein R is the same asabove and R represents an alkyl group having from 1 to 6 carbon atoms orphenyl group. At least 1 mole of the Wittig reagent is used per mole ofthe compound (XIX) or (XX) and preferably from 2 to 10 moles of theWittig agent is used. The reaction is generally carried out in an inertorganic solvent such as ether, benzene, toluene, hexane, dimethylsulfoxide, tetrahydrofuran, methylene chloride or chloroform, at atemperature ranging from 0C. to reflux temperature of the reactionmixture, preferably at room temperature or below and in an inert gasatmosphere, for example, in an argon or helium atmosphere. The reactionis carried out for a period of'5 hours to 3O or dimethylforrnamide, atrelatively low temperatures,

usually at a temperature ranging from -l0C. to room I group may beprepared by reacting the compound hours depending on the temperatureandconcentrati'on of the reaction mixture and the specific Wittigreagent used.

The compound (XXII) may be prepared by reducing The reaction ispreferably carried out in an inert organic solvent such'a's methanol,ethanol, ether, dioxane (XXII) with an acid and reacting the productthus obtained with a compound having the formula X COOR Preparation ofthe compounds (IV) 7 za-cooa A-COOR7 A-COOR R oocoH c c3 03 n oocoa cCHZO-THP x oocoagc CH2OTHP (XIII) (XXIII) (XXIV) C9 Q .v A-COOR7 a oocoac ca -o 'rap a oocoa 'c ca on n oocon c cao VI) XXvII) v (XXV) R oocoa c(XXVIIZ same as above. R re resents an alkano l rou or benzoyl group.TI-IP represents tetrahydropyranyl group.

Each of the above steps may be illustrated as follows:

The compound (XXIII) may be prepared by reacting the compound (XIII)with dihydropyran in the presence of a mineral acid, e.g., hydrochloricacid, hydrobromic acid or an organic acid, e.g., p-toluenesulfonic acid.The reaction is preferably carried out in an inert organic solvent suchas benzene, toluene or chloroform at a temperature ranging from C. toroom temperature.

The compound (XXIV) may be prepared by reducing the compound (XXIII)with a metal hydride compound such as sodium boron hydride, potassiumboron hydride, lithium boron hydride, trimethoxylithium aluminum hydrideand aluminum lithium hydride. The reaction is preferably carried out inan inert organic solvent such as methanol, tetrahydrofuran or ether at atemperature ranging from 0C. to a reflux temperature of the reactionmixture.

The compound (XXV) may be prepared by contacting the compound (XXIV)with a halide or anhydride of an alkanoic acid or benzoic acid, e.g.,acetic anhydride, acetyl chloride, benzoic anhydride, benzoyl chloride.

The compound (XXVI) may be prepared by contacting the compound (XXV)with a dilute acid solution, for example, a dilute solution of aceticacid, hydrochloric acid or sulfuric acid.

The compound (XXVII) may be prepared by contacting the compound (XXVI)with an oxidizing agent, e.g., chromic acid, dimethyl sulfoxide-chlorinecomplex, dimethylsulfoxide-acetic anhydride, N- bromoacetamide andaluminum tert.-butoxide. The reaction is carried out at a temperatureranging 20C. to room temperature in a solvent, e.g., benzene, aceticacid, dichloromethane and aqueous tert.-butanol.

The compound (XXVIII) may be prepared by reacting the compound (XXVII)with a Witting reagent having the formula (R P CH CO R wherein R is thesame as above and R represents an alkyl group from I to 6 carbon atomsor phenyl group. At least 1 mole of the Wittig reagent is used per moleof the compound (XXVII) and preferably from 2 to 10 moles of the Wittigagent is used.

The compound (IV) in which R is an alkyl group and R is hydrogen atommay be prepared by contacting the compound (XXVIII) withan acid such asformic acid, acetic acid. hydrochloric acid or sulfuric acid or with analkali metal compound such as sodium hydroxide, potassium hydroxide orsodium carbonate.

The compound (IV) in which R and R are hydrogen atom may be prepared byreacting the compound (XXVIII) with an alkali metal compound such assodium hydroxide, potassium hydroxide or sodium carbonate.

The compound (IV) in which R is hydrogen atom and R is alkoxycarbonylgroup may be prepared by reacting the compound (XXVIII) with an alkalimetal compound and reacting the product thus obtained with a compoundhaving the formula x cooR wherein X represents a halogen atom, e.g.,chlorine, bromine, iodine and R represents an alkyl group having from 1to 6 carbon atoms in the presence of an alkali metal compound such assodium carbonate, sodium bicarbonate.

The product obtained in each step of the above process may be recoveredfrom the reaction mixture in a conventional means, for example, byevaporating the solvent from the reaction mixture or by adding water andextracting with a water immiscible solvent.

The crude product can be purified by conventional means such asrecrystallization or chromatography.

The following preparations and examples are given for the purpose ofillustration of the present invention. Preparations l and 2 illustratethe preparation of the compound (II). Preparations 3 and 5 illustratethe preparation of the compound (III). Preparation 4 illustrates thepreparation of the compound (IV). Examples 1 and 2 illustrate thepreparation of the compound (I) from the compound (II). Example 3, 4, 6and 7 illustrate the preparation of the compound (I) from the compound(III). Example 5 illustrates the preparation of the compound (I) fromthe compound (IV).

PREPARATION 1 Preparation of 9.5, dioxo-l la-hydroxymethylprost-l 3(trans eno ic acid 1 l-Ethylenedioxy-3,4-dimethoxycarbonylcyclopentane(VI) In 250 ml. of dichloromethane were dissolved I24 g. of3,4-dimethoxycarbonylcyclopentanone and 155 g. of ethyle'neglycol and tothe solution was added dropwise 94 g. of boron trifluoride etherate atO5C. After completion of the addition, the reaction mixture was stirredfor 2 hours at l0-l6C. and next for 1.5 hours at 16-23C. Aftercompletion of the reaction, the re action mixture was added dropwise to1.5 l. of a saturated aqueous sodium bicarbonate containing pieces ofice in order to decompose the excess of the boron trifluoride etherate.The mixture was extracted three times with l l. of ether. The extractwas washedwith a saturated aqueous sodium chloride and a saturatedaqueous sodium bicarbonate and dried over anhydrous sodium sulfate. Thesolvent was distilled off from the extract to give 135.7 g. of thedesired product as colorless oil.

l.R. (liquid film) vmax :l74l, 1438, 1329, 1200,

N.M.R. (CDCl Azppm 3.63, 3.69 (6H, each singlet, cis and trans COOCH3.90 (4H, singlet,

2. l-Ethylenedioxy-trans-3,4-dimethoxycarbonylcyclopentane (VII) In 3200ml of dry benzene was dissolved 178 g. oflethylenedioxy-3,4-dimethoxycarbonylcyclopentane and to the solution wasadded dropwise a sodium methylate solution prepared from 16.8 g. ofmetallic sodium and 730 ml. of absolute methanol in argon atmosphere at5C. After completion of the addition, the solution was stirred for 2hours at 5C. and next for 3 hours at 2022C. After completion of thereaction, the reaction mixture was cooled to 0C. and added to about 2.2l. of ice-water containing 80 ml. of acetic acid under stirring. Thereaction mixture was saturated with sodium chloride and the benzenelayer was separated. The aqueous layer was extracted with 2 l. of etherand l l. of ethyl acetate. The extracts were combined, washed with asaturated aqueous sodium chloride and dried over anhydrous sodiumsulfate. The solvent was distilled off from the extract under reducedpressure to give 173 g. of pale yellow oil. The oil was subjected tovacuum distillation to give 155.8 g. of the pure desired product as oilboiling at 120123C. under 0.05 mm. pressure of mercury.

I.R'. (liquid film) vmax z 1741, 1438, 1329, 1200, 1030.

N.M.R. '(CCl A: ppm, 3.63 (6H, singlet, trans- COOC I I 3.83 (4H,singlet,

3. l -Ethylenedioxy-trans-3,4-dihydroxymethylcyclopentane (VIII) In 400ml. of dry ether was dissolved 78 g. of 1-ethylenedioxy-trans-3,4-dimethoxycarbonylcyclopentane and the resultingsolution was added dropwise to a suspension of 30.3 g. of lithiumaluminum hydride in 300 ml. of dry ether at 5C. After completion of theaddition, the mixture was stirred for 3 hours. After completion of thereaction, 500 ml. of ether saturated with water and 130 ml. of asaturated aqueous sodium chloride were added to the reaction mixturebelow 10C. to decompose the excess lithium aluminum hydride. The etherwas separated from the reaction mixture by decantation. The aqueouslayer was extracted with ether and further subjected to evaporationunder reduced pressure. The residue was extracted with absolute ethanol.All of the extract were combined and dried over anhydrous sodiumsulfate. The solvent was distilled off to give 68.4 g. of the desiredproduct as pale yellow oil.

I.R. (liquid film) vmax 3400, 2900, 1433, 1141, 1013, 950.

N.M.R. (CC1 A: ppm, 3.l53.78 (4H, multiplet, CH OH); 3.80 (4H, singlet,

4.50 (2H, singlet, -Ol-I).

4. M l-Ethylenedioxy-trans-3 ,4- diethoxycarbonyloxymethylcyclopentane(IX) In 1 l. of dry pyridine was dissolved 113 g. of 1-ethylenedioxy-trans-dihydroxymethylcyclopentane and to the solution wasadded dropwise 250 g. of ethyl chloroformate (ClCOOC l-I below 5C. Aftercompletion of the addition, the reaction mixture was stirred for 30minutes at that temperature and next for 2 hours at room temperature.After completion of the reaction, the reaction mixture was added to 2 l.of ice water and the mixture was extracted with ether. The extract waswashed with a saturated aqueous sodium chloride and dried over anhydroussodium sulfate. The solvent was distilled off to give 188.2 g. of thedesired product as pale yellow oil.

I.R. (liquid film) vmax z 1750, 1469, 1403, 1372, 1260, 1010, 949, 875,791.

N.M.R. (CDCl A: ppm, 1.15-1.50 (6H, triplet, -OCH Cl-l 3.88 (4H,singlet,

H CCH I 4.004.35 (8H, multiplet, Cl-I OCOOC H CI-I 5.Trans-3,4-diethoxycarb'6nyloxymethylcyclopentane-l-one (X) In a mixtureof 800 ml. of acetone, 20 ml. of water and 2.5 ml. of 10 hydrochloricacid was dissolved 56.5 g of l -ethylenedioxy-trans-3 ,4-diethoxycarbonyloxymethylcyclopentane and the solution was stirred forone hour at room temperature and further for 2 hours at 50C. Afteraddition of 2.0 g. of p-toluenesulfonic acid. After completion .of thereaction, the reaction mixture was added to 2 l. of ice water andsaturated with sodium chloride. The mixture was extracted with benzene.The extract was washed with a saturated aqueous sodium chloride anddried over anhydrous sodium sulfate. The solvent was distilled off togive 51.0 g. of the desired product as pale yell'ow oil'. The oil wassubjected to column chromatography using 250 g. of silica gel washedwith hydrochloric acid and eluted some amounts of nhexane and nextsuccessively n-hexane-benzene (1:1)-benzene-ethylacetate (:5). Thesolvent was distilled off from the eluate to give 47.3 g. of the desiredproduct as oil.

I.R. (liquid film) vmax"" 1748, 1469, 1408, 1376, 1260, 1009, 877, 792.

N.M.R. (CDCl A: ppm, 1.18-1.50 (6H, triplet, -OCH C I;I 4.30 (4H,singlet, Cl-I- OCOOCl-l Cl-1 4.02-4.41 (41-1, quartette, c"i+ OCOOC l -ICH 6.2-Carboxy-3hydroxymethyl-4aethoxycarbonyloxymethylcyclopentan-1-one-2,3-(I)-lactone (XI) In 700 ml. of dry tetrahydrofuran was dissolved 28.83 g. oftrans-3,4-diethoxycarbonyloxymethylcyclopentan-l-one and to the solutionwas added dropwise a solution of 16.9 g. of potassium tert.-butoxide in900 ml. of dry tetrahydrofuran in an argon atmosphere at -45C. Aftercompletion of the addition. the reaction temperature was slowly elevatedto C. The completion of the reaction was confirmed with chromatography.The reaction mixture was again cooled to -C. and added to about 2 1. ofice water containing 50 ml. of acetic acid under vigorous agitation. Tothe mixture was added sodium chloride and the mixture was extracted withether and benzene. The extract was washed with a saturated aqueoussodium chloride and dried over anhydrous sodium sulfate. The solvent wasdistilled off to give 27.0 g. of pale yellow oil. To the oil was addedether-n-hexane and the mixture was allowed to cool to give 10.5 g. ofthe desired product as crystals. The mother liquor was subjected tocolumn chromatography using silica gel and eluted with benzene to give4.1 g. of crystals. The total yield was 14.6 g. melting point was65-66C.

LR. (Nujol) V max""': 1772, 1747, 1290, 1283, 1258, 1168, 1150, 1029,880, 790.

N.M.R. (CDCI A: ppm, 1.20-1 .46 (3H, triplet, OCH CH 3.00-3.45 (11-1,multiplet,

3.46-3.58 (1H, doublet 1 H cg coocog c 1 m Analysis:

Calculated for C H O C,54.54; H, 5.83

Found C,54.88; H,6.07.

7. 2-(6-Methoxycarbonylhexy1)-2-carboxy-3-hydroxymethy1-4aethoxycarbonyloxymethylcyclopentane-1-one-2,3-(l)-lactone (XII) In 60 ml. of dimethyl sulfoxide was dissolved 6.54 g. of2-carboxy-3-hydroxymethyl-4-ethoxycarbonyloxymethylcyclopentane-1-one-2,3 (F )-lactone and to thesolution was added 4.85 g. of potassium tert.-butoxide in argonatmosphere under cooling and the mixture was stirred for 60 minutes atroom temperature. To the mixture was added 10.9 g. of methyl7-iodoenanthate and the mixture was stirred for 6 hours at roomtemperature. After completion of the reaction, the reaction mixture wasadded to 500 ml. of ice-water containing 27 ml. of acetic acid and themixture was extracted with ethyl acetate and benzene. The extract waswashed with a saturated aqueous sodium chloride and dried over anhydroussodium sulfate. The solvent was distilled off to give 1.5 g. of the paleyellow r: If .1

a I H 3.63 (3H, singlet, COOCH 4.05-4.6 (6H, multiplet,

H cg coocon c" 8. 2a-( 6-Methoxycarbonylhexyl)-3B-hydroxymethyl-4a-ethoxycarbonyloxymethylcyclopentane- 1 -one (XIII) In a solution of90 ml. of dioxane, 24 ml. of water and 2.43 g. of potassium carbonatewas dissolved 6.12 g. of 2-( 6-methoxycarbonylhexyl )-2-carboxy-3-hydroxymethyl-4- ethoxycarbonyloxymethylcyclopentane-1-one-2,3(1)-lactone and the resulting solution was stirred in argon atmosphere for 3days at room temperature. After completion of the reaction, the reactionmixture was added to 500 m1. of ice-water containing 10 ml. of aceticacid. The mixture was extracted with ethyl acetate. The extract waswashed with a saturated aqueous sodium chloride and dried over anhydroussodium sulfate. The solvent was distilled off to give 6.1 g. of paleyellow oil. The oil was subjected to column chromatography using 48 g.of silica gel and eluted with some amounts of n-hexane and nextsuccessively with nhexane-benzene 1:2)-benzene-ethyl acetate (99:1 Theeluates with n-hexane-benzene (1:2)-benzeneethyl acetate (99:1 werecollected and the solvent was distilled off to give 4.50 g. of thedesired product as oil.

LR. (liquid film) V max": 3540, 2940, 1742, 1440, 1370, 1258, 1172,1008, 873, 792.

N.M.R. (CDCl Azppm: 0.90-1.34 (3H, triplet, OCH C I' I;;); 3.44 (3H,singlet, COOCH 3.50-4.20 (6H, multiplet, CH Q H and -CH- OCOOQI-I CH5.30 (1H, singlet, C1-I O I-I). m

9.2a-(6-Methoxycarbonylhexyl)-3B-formyl-4aethoxycarbonyloxymethylcyclopentane-1 -one (XIV) In m1. of dichloromethane was dissolved 1.53 g. of 2a-(6-methoxycarbonylhexyl)-3B-hydroxymethy1-4aethoxycarbonyloxymethylcyclopentane-l-oneand to the solution was added 10 g. of chromic anhydridepyridine complex(Collins reagent). The mixture was stirred for 10 minutes at roomtemperature. After completion of the reaction, 100 ml. of ether wasadded to the reaction mixture and the mixture was stirred for a whileand filtered with Hyflo Super Cel: (trade name of Johns Manville SalesCorp.). The precipitates was washed with ether and the washing wascombined .with the filtrate. After cooling, the organiclayer was washedsuccessively with a cooled 2% aqueous sodium hydroxide, a cooled 2%aqueous hydrochloric acid, a cooled aqueous sodium bicarbonate and asaturated aqueous sodium chloride, respectively, and dried overanhydrous sodium sulfate. The solvent was distilled off from the organiclayer to give 1.23 g. of the desired product as pale yellow oil.

l.R. (liquid film) vmax 2930, 1742, 1462, 1440, 1404, 1370, 1259, 1170,1008,874, 792.

N.M.R. (CDCl3) A: ppm, 1.20-1.41 (3H, triplet, OCH C 1:1 3.68 (3H,singlet, -COOC I -I 4.06-4.43 (4H, multiplet, -CI-I OCOOCl-I CI-I 9.921H, singlet, cgo

10. 2a-(6-Carboxyhexy1)-3,8-formy1-4ahydroxymethylcyclopentane-1-one(XV) In a solution of 35 ml. of methanol, 7 ml. of water and 3.3 ml. of10% aqueous potassium hydroxide was dissolved 712 mg. of2a'-(6-methoxycarbonylhexyl)-3;8-formyl-4a-ethoxycarbonyloxymethylcyclopentanel-one and the resultingsolution was stirred for 4 hours at room temperature in an argonatmosphere. After completion of the reaction, the reaction mixture wasadded to 200 ml. of ice water containing 2 ml. of acetic acid andextracted with ethyl acetate. The extract was washed with a small amountof an aqueous sodium chloride and dried over anhydrous sodium sulfate.The solvent was distilled off to give 315 mg. of the desired product aspale yellow oil.

I.R. (liquid film) 11 max""": 3470, 2700, 1720.

l 1 9, l5-Dioxo-l la-hydroxymethylprostl3(trans)enoic acid (II) In 15ml. of ether was dissolved 310 mg. of 2a-(6-carboxyhexyl)-3,B-formyl-4a-hydroxymethylcyclopentane-l-one and to thesolution was added 430 mg. of 2-oxoheptylidene tri-n-butylphosphorane.The mixture was stirred for 12 hours at room temperature in an argonatmosphere. After completion of the reaction, the solvent was distilledoff from the reaction mixture under reduced pressure to give 740 mg. ofthe desired product as yellowish orange oil. The oil was subjected tocolumn chromatography using 6 g. of silica gel and eluted withbenzene-benzene-ethyl acetate (95:5). The eluates with benzene-ethylacetate (95:5) were collected and the solvent was distilled off to give372 mg. of the desired product.

I.R. (liquid film) 11 max"" 3500, 2950, 1737, 1630, 1460, 1408, 1380,1090, 981, 902, 725.

N.M.R. (CDCl Azppm, 0.80-1.05 (3H, triplet, CH C I-I 3.34-3.73 (2H,multiplet, -(;l-I OH); 5.78 (2H, singlet, -OI-I and COOH), 6.07-6.35(1H, doublet,

PREPARATION 2 g Methyl 9, l S-dioxo-l la-ethoxycarbonyloxymethylprost-13(trans )-enoate (II) In 45 ml. of ether was dissolved 1.20 g. of2a-(6- methoxycarbonylhexyl 3B-formyl-4aethoxycarbonyloxymethylcyclopentane- 1 -one (XIV) and to thesolution was added 1.28 g. of 2- oxoheptylidenetri-n-butylphosphoraneand the mixture was stirred for 17 hours at room temperature in an argonatmosphere. After completion of the reaction,

the solvent was distilled off from the reaction mixture under reducedpressure to give 2.52 g. of oil. The oil was subjected to columnchromatography using 20 g. of silica gel and eluted successively withn-hexane-nhexane-benzene (5:1 The eluates were collected and the solventwas distilled to give 1.52 g. of the desired product as oil.

LR. (liquid film) v max"': 2940, 1745, 1700, 1678, 1631, 1460, 1405,1370, 1256, 1169, 1008, 872, 791.

N.M.R. (CDCl Azpprn 0.80-1.10 (3H, triplet, -CI-I CH 1.16-1.41 (3H,triplet, -OCI-I C lj 3.68 (3H, si ri glet, -COOC I;I 4.03-4.40 (4H,multiplet, -CI OCOOCI CH 6.08-6.33 (1H, doublet,

6.55-6.94 (ll-l, quartette,

H ll 0 PREPARATION 3 Preparation of 9-oxo- 1 l a-hydroxymethyl- 1 5a(or,8)-hydroxyprostl3(trans)-enoic acid (111) l l-Ethylenedioxy-2oz-(6-methoxycarbonylhexyl)-3B-hydroxymethyl-4a-ethoxycarbonyloxymethylcyclopentane (XVIII) To amixture of 2.02 g. of methoxycarbonylhexyl )-3IS-hydroxymethyl-4aethoxycarbonyloxymethylcyclopentanel-one (XIII), 3.5g. of ethylene glycol and 6 ml of dichloromethane was added dropwise 3.0g of boron trifluoride diethyl ether complex under ice-cooling. Aftercompletion of the addition, the mixture was stirred for 2 hours at l0C.-1 5C. and then for 3 hours at 0C. After completion of the reaction,the reaction mixture was poured into a saturated aqueous sodium chloridecontaining pieces ice and the mixture was saturated with sodiumchloride. The mixture was extracted with ether and the extract was driedover anhydrous sodium sulfate. The solvent was distilled off to give 2.3g. of pale yellow oils. The oilswere subjected to column chromatographyusing 12,5 g. of silica gel and eluted some amounts of n-hexane and nextsuccessively with nhexane benzene 2: l-l :l The eluates with nhexanebenzene 2: 1-1 :1 were collected and the solvent was distilled to give1.25 g. of the desired product as oil.

[.R. (liquid film) 11 max 3520. 2930, 1788. 1740. 14401370. 1255. 1100.1010, 951. 874.791.

N.M.R. (CDCL A: ppm 3.70 (3H, singlet, COOC l;I cyclopentane-l-one(XIII), 3.5 g. of ethylene glycol and 6 ml. of dichloromethane was addeddropwise 3.0 g. of boron trifluoride diethyl ether complex underice-cooling. After completion of the addition, the mixture was stirredfor 2 hours at 10)\ C.-lC. and then for 3 hours at 0C. After completionof the reaction, the reaction mixture was poured into a saturatedaqueous sodium chloride containing pieces ice and the mixture wassaturated with sodium chloride. The mixture was extracted with ether andthe extract was dried over anhydrous sodium sulfate. The solvent wasdistilled off to give 2.3 g of pale yellow oils. The oils were subjectedto column chromatography using 12.5 g. of silica gel and eluted someamounts of n-hexane and next successively with n-hexane-benzene 2:l-1 :1(2: 1-1 :1 were collected and the solvent was distilled to give 1.25 g.of the desired product as oil.

I.R. (liquid film) 11 max"': 3520, 2930, 1788, 1740, 1440, 1370, 1255,1100, 1010, 951, 874, 791.

N.M.R. (CDC1 A: ppm, 3.70 (3H, singlet, COOCII;,); 3.91 (4H, singlet,

4.00-4.50 (6H, multiplet, -C I -I OI-I and -C I:l O- COOC I-I CH 2. 1-Ethylenedioxy-2a-( 6-methoxycarbonylhexyl)-3/3-formyl-4a-ethoxycarbonyloxymethylcyclopentane(XlX) In 60 ml. ofdichloromethane was dissolved 1.04 g. of l-ethylenedioxy-2a-(6-methoxycarbonylhexyl )-3B-hydroxymethyl-4a-ethoxycarbonyloxymethylcyclopentame and to the solutionwas added 6.7 g. of anhydrous chromic acid-pyridine complex (Collinsreagent) followed by stirring for 10 minutes at room temperature. Aftercompletion of the reaction, 100 ml. of ether was added to the reactionmixture followed by stirring and the mixture was .filtered with HyfloSuper Cel. The precipitates were washed with ether and the washing wascombined with the filtrate. The organic layer was cooled andwashedsuccessively with a cooled 2% aqueous sodium hydroxide, a cooled 2%aqueous hydrochloric acid, a cooled 5% aqueous sodium bicarbonate and asaturated aqueous sodium chloride, respectively, and dried overanhydrous sodium sulfate. The solvent was distilled ofi from the organiclayer to give 935 mg. of the desired product as pale yellow oil.

I.R. (liquid film) 11 max" 2940, 1784, 1740, 1440, 1370, 1255, 1165,1100, 1015, 951, 875, 791.

N.M.R. (CDCl A: ppm, 3.68 (3H, singlet, COOC I 3.92 (4H, singlet,

4.00-4.50 (4H, multiplet, Cfl OCOOCI-I CH 9.60-9.90 (ll-I, multiplet, CII O The eluates with n-hexane-benzene LII 3. 1-Ethylenedioxy2a-(6-carboxyhexyl )-3B-formyl- 4a-hydroxymethylcyclopentane (XX) In amixture of m1. of methanol, 13 ml. of water and 7 ml. of a 10% aqueouspotassium hydroxide was dissolved 1.60 g. of l-ethylenedioxy-2a-(6-methoxycarbonylhexyl )-3 a-formyl-4oeethoxycarbonyloxymethylcyclopentanefollowed by stirring for 4 hours at room temperature in an argonatmosphere. After completion of the reaction, the reaction mixture wasadded to ice water containing 4 ml. of acetic acid with vigorousagitation and the mixture was extracted with ethyl acetate. The extractwas washed with a small amount of a saturated aqueous sodium chlorideand dried over anhydrous sodium sulfate. The solvent was distilled offfrom the extract to give 860 mg. of the desired product as a pale yellowoil.

I.R. (liquid film) 11 max ""1 3450, 2710, 1720.

4. 9-Ethylenedioxy-1 la-hydroxymethyll 5-oxoprostl3(trans)-enoic acid(XXI) In 30 ml. of ether was dissolved 620 mg. oflethylenedioxy-2o1-(6-carboxyhexyl)-3B-formyl-4ozhydroxymethylcyclopentaneand to the solution was added 760 mg. of2-oxoheptylidenetri-nbutylphosphorane followed by stirring for 13 hoursat room temperature in an argon atmosphere. After completion of thereaction, the solvent was distilled 'off from the reaction mixture togive 1.49 g. of yellowish orange oils. The oil was subjected to columnchromatography using 12 g. of silica gel and eluted with some amounts ofbenzene and next successively with benzene-ethyl acetate (99:198:2). Theeluates with the latter solvent were collected and the solvent wasdistilled off to give 705 mg. of the desired product.

I.R. (liquid film) v max"'*: 3450, 1710, 1678, 1631. N.M.R. (CDCl A:ppm, 6.07-6.33 (1H, quartette,

6.56-6.93 (1H, quartette,

H r 11 H '5. 9-Ethylenedioxyl 1 a-hydroxymethyll S-hydroxy prostl3-(trans)-enoic acid (XXII) In 25 ml. of ethanol was dissolved 615 mg.of 9- ethylenedioxy-l 1 oz-hydroxymethyll 5-oxoprost- 13(trans)-enoicacid and to the solution was added a mixture of 230 mg. of sodium boronhydride and 13 ml.

of ethanol under ice cooling followed by stirring for 2 hours at 05C.After completion of the reaction, the reaction mixture was poured into100 ml. of ice water and the pH adjusted to 4.0 by addition of aceticacid. The reaction was extracted with ethylacetate and the extract wasdried over anhydrous sodium sulfate. The solvent was distilled off togive 603 mg. of the desired product as pale yellow oils.

LR. (liquid film) 11 max'": 3450, 2940, 1717, 1460, 1260, 1154, 1030,972, 95.1.

N.M.R. (CDCl A: ppm, 0.60 l.10 (3H, triplet, CI-I C I;I 3.94 (4H,singlet,

5.90 (3H, singlet, O& and COO! -l 6. 9-Oxo-1 la-hydroxymethyl-lSa (orB)-hydroxyprost-13(trans)-enoic acid (lll) To a mixture of 12 ml. ofacetone, 2.5 ml. of water and mg. of p-toluenesulphonic acid was added596 mg. of 9-ethylenedioxy-1 la-hydroxymethyl-IS-hydroxyprost-l3(trans)-enoic acid followed by stirring for 1 hour atroom temperature. After completion of the reaction, the reaction mixturewas dried over 5 mg. of anhydrous sodium acetate and the solvent wasdistilled off. To the residue was added about ml. of ice water and themixture was saturated with sodium chloride and extracted with ethylacetate. The extract was washed with a saturated aqueous sodium chlorideand dried over anhydrous sodium sulfate. The solvent was distilled offfrom the extract to give 563 mg. of pale yellow oils. The oils weresubjected to column chromatography using 5.6 g. of silica gel and elutedwith some amounts of benzene and next with benzeneethylacetate (5:1 Theeluates with the latter solvent were collected and the solvent wasdistilled off to give 163 mg. of 9-oxo-11a-hydroxymethyl-15a-hydroxyprost-13(trans)-enoic acid. The eluates withbenzeneethyl acetate (3:2) were collected and the solvent was distilledoff to give 150 mg. of the mixture of 9-oxo- 1 1 a-hydroxymethyl- 1SB-hydroxyprost- 1 3(trans)-enoic acid and 9-oxo-11a-hydroxymethyl-15a-hydroxyprost- 13(trans)-enoic acid. The eluateswith benzene-ethyl acetate (1:1) were collected and the solvent wasdistilled off to give 108 mg. of 9-oxo-1 loz-hydroxymethyl-ISa-hydroxyprost-l3(trans)-enoic acid. The infrared absorption spectrumand nuclear magnetic resonance of thus obtained 9-oxo-1la-hydroxymethyl-l 5B- hydroxyprost- 1 3(trans)-enoic acid, 9-oxo-llahydroxymethyll 5a-hydroxyprost- 1 3(trans)-enoic acid and the mixturethereof were in accordance with each other.

LR. (liquid film) 11 max"'': 3400, 2940, 1730, 1460, 1405, 1260, 1163,1052, 1018, 972, 726.

N.M.R. (CD COCD A: ppm, 0.70-1.10 (3H, triplet, -CH C l:l 3) 3.204.3O(6H, multiplet, COO ll Cg0li, C l;l O); 5.54-5.75 (2H. multiplet,

9-Oxo-1 1 a-hydroxymethyl-l Sa-hydroxyprost- 13( trans)-enoic acid wasobtained as semicrystals melting at 6567C. by allowance of cooling.

PREPARATION 4 Preparation of methyl 9 {-hydroxy-lla-hydroxymethyl-15-oxoprost-l3(trans)- enoate (1V) 11-Oxo-2oz-methoxycarbonylhexyl-3 ,8-tetrahydropyranyloxymethyl-4aethoxycarbonyloxymethylcyclopentane (XXlll)To 3.584 g. of 1-oxo-2a-methoxycarbonylhexyl-3B-hydroxymethyl-4a-ethoxycarbonyloxymethylcyclopentane in 50 ml. of drybenzene were added 1.68 g. of dihydropyran and 15 mg. ofp-toluenesulfonic acid and the mixture was stirred for 30 minutes underice cooling and for 30 minutes at room temperature. To the mixture wasadded 10 ml. of 2% aqueous sodium carbonate. The benzene layer waswashed with saturated aqueous sodium chloride and dried over anhydroussodium sulfate and the solvent was distilled off to give 5.1 g. of oil.The oil was subjected to column chromatography using 50 g. of aluminum(grade ll, Voelm. Co.) and eluted with n-hexane-benzene (4:1)-benzene togive 4.12 g. of the desired product.

l.R. (liquid film) 11 max"" 1745, 1119, 1028.

N.M.R. (CDCl,,) :1: ppm, 4.72-4.58 (1H, multiplet,

3.65 (3H, singlet, Coocg 2. l fi-hydroxy-2a-methoxycarbonylhexyl-3B-tetrahydropyranyloxymethyl-4aethoxycarbonyloxymethylcyclopentane (XXlV)and 1f-acetoxy-2oz-methoxycarbonylhexyl-3 B-tetrahydropyranyloxymethyl-4aethoxycarbonyloxymethylcyclopentane (XXV)4.10 g oftetrahydropyranyloxymethyl-4aethoxycarbonyloxymethylcyclopentane in 50ml. of absolute methanol was reduced with 540 mg. of sodium boronhydride under ice cooling to give 4.19 g. of 15-hydroxy-Za-methoxycarbonyhexyl-3B-tetrahydropyranyloxymethyl-4aethoxycarbonyloxymethylcyclopentane.

The product thus obtained was acetylated with 10 ml. of acetic anhydridein 50 ml. of dry pyridine at room temperature to give 4.82 g. of oil.The oil was subjected to column chromatography using 40 g. of silica geland eluted with n-hexane-benzene (1:8)-benzene to give 4.01 g. of1-acetoxy-Za-methoxycarbonylhexyl-3B-tetrahydropyranyloxymethyl-4aethoxycarbonyloxymethylcyclopentane.

LR. (liquid film) v max"" 1742, 1120, 1030.

N.M.R. (CDCl A: ppm, 4.74-4.60 (1H, multiplet,

5.31-4.75 (ll-l, multiplet,

H OAC 1-oxo-2a-methoxycarbonyhexyl-3B- 2.00 (3H, singlet. OCCfi 3.67(3H, singlet, cooc 1 &

3. 1E-Acetoxy-Za-methoxycarbonylhexyl-3,8-

hydroxymethyl-4a-ethoxycarbonyloxymethylcyclopentane (XXVI) In a mixtureof 40 m1. of acetic acid, 40 ml. of water and 6 ml. of tetrahydrofuranwas dissolved 4.00 g. of 1f-acetoxy-2a-methoxycarbonylhexyl-3B-tetrahydropyranyloxymethyl-4w ethoxycarbonyloxymethylcyclopentane andthe solution was stirred for 4.5 hours at 45C. The reaction mixture waspoured into ice water and extracted with ethyl acetate, washed with asaturated aqueous sodium chloride, dried over anhydrous sodium sulfateand the solvent was distilled off to give 3.86 g. of oil. The oil wassubjected to column chromatography using 30 g. of silica gel and elutedwith benzene-ethyl acetate (99:1 )-(90:l0) to give 3.01 g. of thedesired product.

LR. (liquid film) v max z 3400, 1704.

N.M.R. (C DCl3) 6: ppm, 5.28-4.77 (1 H, multiplet.

3.67 (3H, singlet, -COOCfl 2.00 (3H, singlet, O- COCI I 1.100.78 (3H,triplet, -CH O-COOCH- 2 C l i 4.l-Acetoxy-Za-methoxycarbonylhexyl-3,8-formyl-4a-ethoxycarbonyloxymethylcyclopentane (XXVII) and methyl 9lf-acetoxy-lla-ethoxycarbonyloxymethyl l5-oxoprost-13(trans)-enoate (XXVIII) To 3.00g. of lg-acetoxy-Za-methoxycarbonylhexyl-3B-hydroxymethyl-4a-ethoxycarbonyloxymethylcyclopentane in 150 ml. ofdry methylene chloride was added 19 g. of Collins reagent under icecooling and stirred for minutes at room temperature. After completion ofthe reaction, 200 ml. of ether was added to the reaction mixture andmixture was filtered with Hyflo Super Cel. The precipitates were washedwith ether and the washing was combined with the filtrate. The filtratewas washed with 5% aqueous sodium carbonate, 2% aqueous hydrochloricacid, 5% aqueous sodium bicarbonate and a saturated aqueous sodiumchloride, respectively and dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure to give 2.76 g. of1-acetoxy-2amethoxycarbonylhexyl-3/3-formyl-4aethoxycarbonyloxymethylcyclopentane(XXVII).

The product thus obtained was dissolved in 60 ml. of anhydrous ether andto the solution is added 2.80 g. of2-oxoheptylidene-tri-n-butylphosphorane. The mixture was stirred at roomtemperature in an argon atmosphere for 15 hours. The solvent wasdistilled off under reduced pressure to give 5.51 g. of oil. The oil wassubjected to column chromatography using 45 g. of silica gel and elutedwith n-hexane nhexane -benzene (5: l to give 2.98 g. of methyl9-acetoxy-l 1aethoxycarbonyloxymethyl-l5-oxoprost13(trans)- enoate(XXVIII).

l.R. (liquid film) 11 max"' 1745. 1676. 1630.

N.M.R. (CDC1;,) A: ppm. 6.946.52 (1H, quartette,

6.25-6.00 (1H. doublet,

n W l 3.67 (3H, singlet, COOCfi 2.00 (3H, singlet, O- COCH 5. methyl9oz( and B)-hydroxy-l la-hydroxymethyll5-oxoprost-13(trans)-enoate (IV)In a mixture of 30 ml. of methanol, 10 ml. of water and 2.8 ml. of 20%aqueous potassium hydroxide was dissolved 1.02 g. of methyl9fi-acetoxy-l 1ozethoxycarbonyloxymethyl-15-oxoprostl 3 trans enoate andthe solution was stirred at room temperature for 2 hours. The reactionmixture was neutralized by addition of acetic acid. The product wasreacted with diazomethane in acetic anhydride to give 810 mg. of oil.The oil was subjected to column chromatography using 8.0 g. of silicagel and eluted with benzene ethyl acetate (85:15) to give 351 mg. ofmethyl 9ahydroxy-l la-hydroxymethyl-l5-oxopr0st- 13(trans)enoate andwith benzene ethyl acetate (60:40) to give 307 mg. of methyl9a-hydroxy-11ahydroxymethyll 5-oxoprostl 3(trans)-enoate.

I.R. (liquid film) vmax' 3400, 1744, 1677, 1630.

N.M.R. (CDClflfizppm, 6.96-6.50 (1H, quartette.

6.266.02 l H, doublet,

3.68 (3H, singlet, COOCl-b) PREPARATION 5 Preparation of 9-0xo-llwhydroxymethyl-15u(and 8)-hydroxy16.16-dimethylpr0st-13(trans)-enoicacid (III) 1. Methyl 9-ethylenedioxy-11aethoxycarbonyloxymethyl-15-oxo-16.16-dimethylprost- 1 3(trans)-enoate(XXI) Toa solution of 2.5 g. of l-ethylenedioxy-2a-(6-methoxycarbonylhexyl )-3 ,B-formyl-4aethoxycarbonyloxymethylcyclopentanein 40 ml. of dry tetrahydrofuran was added 2.8 g. of 2-oxo-3.3-dimethylheptylidene-tri-n-butylphosphorane and the mixture was refluxedfor hours in an argon atmosphere. After completion of the reaction, thesolvent was distilled off from the reaction mixture. The residue wassubjected to column chromatography using 60 g. of silica gel and elutedwith 5- 1 0% ethyl acetate in benzene to give the desired product.

[.R. (liquid film) v max"" 1740. 1695. 1625.

N.M.R. (CDCIQ) A: ppm. 3.70 (3H. singlet. (I11 1.10 (3H, singlet.'Cljn); 1.05 (3H. singlet. -C

2. Methyl 9-ethylenedioxy-l 1aethoxycarbonyloxymethyl-15-hydr0xy-16.16-dimethylprost-l 3(trans)-enoate (XXII) To 1.91 g. of methyl9-ethylenedioxy-1 1ozethoxycarbonyloxymethyl-l-oxo-16,16-dimethylprost-13(trans)enoate in 60 ml. of methanol was added 240 mg.of sodium boron hydride under ice cooling and the mixture was stirredfor 2 hours at room temperature. After completion of the reaction, themixture was made acidic by addition of acetic acid and extracted threetimes with ethyl acetate. The extract was dried over anhydrous sodiumsulfate and the solvent was distilled off. The residue was subjected tocolumn chromatography using 20 g. of silica gel and eluted with -20%ethyl acetate in benzene to give 1.8 g. ofthe desired product.

I.R. (liquid film) vmax"" 3500, 1740, 1260 N.M.R. (CDClg) A: ppm, 0.90(3H, singlet, 3%,), 0.82 (3H, singlet, -CI;I

3. 9-Ethylenedioxy-1 la-hydroxymethyl- 1 5ghydroxy-l6,16-dimethylprost-1 3(trans)-enoic acid (XXII) To a solution of 40 ml.of 5% aqueous sodium hydroxide and 60 ml. of methanol was added 1.68 g.of methyl 9-ethylenedioxy-l 1aethoxycarbonyloxymethyl-15-hydroxy-l 6,16-dimethylprost-13(trans)-enoate and the mixture was stirred for 2 hoursat room temperature. After completion of the reaction, the mixture wasmade acidic by addition of acetic acid and extracted with ethyl acetate.The solvent was distilled off to give 1.4 g. of the desired product.

4. 9-Oxo-1 la-hydroxymethyl- 1 5a( and ,8)-hydroxy-16,16-dimethylprost-13(trans)-enoic acid (ill) In a mixture of 15 ml. ofacetic acid and 15 ml. of water was dissolved 1.33 g. of9-ethylenedioxy-1 lozhydroxymethyl-l SE-hydroxy- 1 6, l 6-dimethylprost-13(trans)-enoic acid and the solution was stirred for 2 hours at roomtemperature. The mixture was extracted with ethyl acetate and theextract was dried over anhydrous sodium sulfate and the solvent wasdistilled off. The residue was subjected to column chromatography usingg. of silica gel and eluted with 40-60% ethyl acetate in benzene to give500 mg. of the ISa-hydroxy compound and 600 mg. of theISB-hydroxycompound as oil.

ISa-hydroxy compound I.R. (liquid film) z/max 3450, 1740.

N.M.R. (CD COCD A: ppm, 5.7 (2H, broad); 0.91 (3H, singlet, -C I; I 0.88(3H, singlet, {ll-l3)- ISB-hydroxy compound LR. (liquid film) 11 max":3450, 1740.

N.M.R. (CD COCD A: ppm, 5.7 (2H, broad); 051 (31-1, singlet, -CH;;);0.87 (3H. singlet, -CH

EXAMPLE 1 l 5-Dihydroxy-1 la-hydroxymethylprost- 1 3(trans enoic acid Toa solution of 170 mg. of 9,15-diox o-l1ahydroxymethylprost-l3(trans)-enoic acid in 8 of ethanol was added 70mg. of sodium boron hydride in 4 ml. of ethanol under ice cooling andthe mixture was stirred for 2 hours. After completion of the reaction,the pH of the reaction mixture was adjusted to 3.5-4.0 by addition ofacetic acid at 0C. and the solvent was distilled off from the reactionmixture under reduced EXAMPLE 2 Methyl 9g, 1 5-clihydroxy- 1la-ethoxycarbonyloxymethylprost- 1 3 trans )-enoate To a solution of 400mg. of methyl 9,15-dioxo-1laethoxycarbonyloxymethylprost-l3(trans)-enoate in 20 ml. of ethanol wasadded 134 mg. of sodium boron hydride in 8 ml. of ethanol under icecooling and the mixture was stirred for one hour. After completion ofthe reaction, about ml. of ice water containing 1.8 m1. of acetic acidwas added to the reaction mixture. The mixture was extracted with ethylacetate and the extract was dried over anhydrous sodium sulfate. Thesolvent was distilled off to give 425 mg. of the desired product as paleyellow oils.

LR. (liquid film) V max"": 3480, 3200, 2930, 1742, 1.624, 1400, 1330,1250, 1090, 1008, 873, 791, 723.

N.M.R. (CDCl A: ppm, 0.80-1.05 (3H, multiplet, -C1-I Cfi 3.66 (3H,singlet, COOC I;I 3.80-4.80 (6H, multiplet, CHOH and CI-I OCOOCl-I CH5.50 (2H, singlet, M m

EXAMPLE 3 (and B), 15 a-Dihydroxy- 1 1 ahydroxyrnethylprost- 1 3(trans)-enoic acid To a solution of 0.7 g. of methyl 9-oxo-1 1ahydroxymethyl- 1Sa-hydroxyprostl 3(trans)-enoate in 20 m1. of absolute methanol wasadded 70 mg. of sodium boron hydride under ice cooling and the mixturewas stirred for 1 hour in ice bath. After completion of the reaction,the reaction mixture was diluted with a cold 2% aqueous hydrochloricacid and subjected to salting out by addition of sodium chloride. Themixture was extracted three times with m1. of ethyl acetate. The organiclayer was washed two times with saturated aqueous sodium chlroide anddried over anhydrous sodium sulfate. The solvent was distilled off togive 0.7 g. of methyl 9a (and B), l5oz-dihydroxy-11ahydroxymethylprost-l3(trans)-enoate as oil. The oil was subjected to columnchromatography using 21 g. of silica gel and eluted successively with100-200 ml. of benzene-ethyl acetate (5:5, 4:6, 3:7, 2:8, 1:9, 0:10).The eluates with benzene-ethyl acetate (4:6-218) were collected and thesolvent was distilled off. The

residue was recrystallized from ethyl acetate-n-hexane to give 210 mg.of methyl 9a. la-dihydroxy-1lahydroxymethylprostl 3(trans )-enoatemelting at 68-69C. The eluates with benzene ethyl acetate (1:9-0110)were collected and the solvent was distilled off. The residue wasrecrystallized from acetate-nhexane to give 280 mg. of methyl 9B.l5a-dihydr0xyl la-hydroxymethlprost-l 3(trans)-enoate melting at66.5-67.5C. 9a-hydroxy compound IR. (KBr) V max" 3300, 1741.

N.M.R. (CD COCD A: ppm, 5.46 (2H, multiplet,

4.07-3.95 (2H, multiplet,

I I--\ I" Oh j 7 I HO H 3.60 (3H, singlet, -COOCH 3.50 (2H, multiplet,qrg oH 0.90 (3H, triplet?C l- I 9B-hydroxy compound IR. (KBr) V max":3300, 1740. N.M.R. (CD COCD Azppm, 5.46 (2H, multiplet,

4.00-3.80 (2H, multiplet,

nu :1 I

1 HO H 3.60 (3H, singlet, -COOCLI 3.45 (2H, multiplet, C l;l OH); 0.90(3H, triplet, C l;l

2. 9a, 15a-Dihydroxy-lloz-hydroxymethylprostl3(trans)enoic acid In 10ml. of methanol was dissolved 210 mg. of methyl 9a, l5a-dihydroxy-1la-hydroxymethylprost- 13(trans)-enoate with stirring in ice bath. Tothe solution was added 10 ml. of 5% aqueous sodium hydroxide and thesolution was stirred for 30 minutes at room temperature. Then, reactionmixture was diluted with 100 ml. of ice water, neutralized with dilutedaqueous hydrochloric acid, subjected to salting out by addition ofsodium chloride and extracted three times with ml. of ethyl acetate,respectively. The organic layer was 4.06 (2H, multiplet,

3.50 (2H, multiplet, C L1 OH), 0.90 (3H, triplet,

Mass spectram M 370 Using the above procedure, but replacing methyl 9a,1 Sa-dihydroxy- 1 1 a-hydroxymethylprostl 3 (trans- )enoate by methyl9oz, ISa-dihydroxy- 1 1ahydroxymethylprost-l3(trans)-enoate, there wasob tained 9,8. ISa-dihydroxy-l la-hydroxymethylprostl3(trans)enoic acid.

IR. (KBr) 11 max'" 3300. 2700. 1715, 975.

N.M.R. (CD COCD A: ppm, 5.46 (2H, multiplet,

3 .75 (2H, multiplet,

OH H

EXAMPLE 4 9oz( and ,8), 1 5 ,B-Dihydroxy-l la-hydroxymethylprost- 13(trans)- enoic acid 1. Methyl 9a(and B), ISB-dihydroxy-l1ahydroxymethylprost- 1 3( trans)-enoate To a solution of 1.09 g. ofmethyl 9-oxo-11ahydroxymethyll 5 ,Bhydroxyprostl 3(trans)-enoate in 25ml. of absolute methanol was added 109 mg. of sodium boron hydride underice cooling and the mixture was stirred for 1 hour in ice bath. Aftercompletion of the reaction, the mixture was diluted with a cooled 2%aqueous hydrochloric acid and subjected to salting out by addition ofsodium chloride. The mixture was extracted three times with ml. of ethylacetate. The organic layer was washed two times with saturated aqueoussodium chloride and dried over anhydrous sodium sulfate. The solvent wasdistilled off to give 1.09 g. of methyl 95, ISB-dihydroxy-lla'hydroxymethylprost-l3(trans)-enoate as oil. The oil was subjected tocolumn chromatography using 30 g. of silica gel and 4.10 (2H, multiplet.

so, m I

3.65 (3H, singlet, COOCLI 3.56 (2H, broad, singlet, C OH 2.56 (3H,broad, singlet, 30H); 0.90 (3H, triplet. C 9B-hydroxy compound LR.(liquid film) v max"" 3350. I740.

N.M.R. (CDCI A: ppm, 5.53 (2H, multiplet,

OH H

3.874. l 0 (2H. multiplet.

OH H

3.67 (3H, singlet, COOC ll 3.53 (2H, multiplet. C h- OH 2.40 (3H, broadsinglet. 3.0H); 0.90 (3H, triplet. -C l ;l

2. 9a. 1 SB-Dihydroxy-l la-hydroxymethylprostl3(trans)-enoic acid In 10ml. of methanol was dissolved 330 mg. of methyl 901. l SB-dihydroxyl la-hydroxymethylprostl3(trans)-enoate with stirring in ice bath. To thesolution was added 7 ml. of 5% aqueous sodium hydroxide and the solutionwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with 100 ml. of ice-water. neutralized with dilute hydrochloricacid, subjected to salting out by addition of sodium chloride andextracted three times with 50 ml. of ethyl acetate respectively. Theorganic layer was washed with saturated aqueous sodium chloride anddried over sodium sulfate. The solvent was distilled off to give 340 mg.of oily residue. The residue was crystallized from ethylacetate-n-hexane to give 283 mg. of the desired product as crystallsmelting at 87.588.5C.

LR. (KBr) vmax"'" 3450, 3350, 2630. 1710, 1260, 963.

N.M.R. (CD COCD3) A: ppm, 5.50 (2H, multiplet.

4.10 (2H, multiplet,

3.50 (2H, multiplet, C&OH); 0.90 (3H, triplet, 1

Mass spectrum: M 370 Using the above procedure, but replacing methyl9a,- ISB-dihydroxy-l la-hydroxymethylprostl 3 (trans)- enoate by methyl9B,l5B-dihydroxy-l 1ahydroxymethylprost-l3(trans)-enoate. there wasobtained 9,8,15B-dihydroxy-l la-hydroxymethylprostl3(trans)-enoic acid.

IR. (KBr) 11 max"" 3300. 2700, 1715, 975.

N.M.R. (CD COCD A: ppm, 5.48 (2H, multiplet,

3.65-4.05 (2H. multiplet.

3.47 (2H. multiplet. Cl ;I- OH); 0.90 (3H, triplet, 431.). Massspectrum: M* 370 EXAMPLE 5 9a(and ,8),l5a(and B )-Dihydroxy-lla-hydroxymethylprostl 3 trans enoic acid 1. Methyl 9a (and B). 156!(and B)-dihydr0xy-l lahydroxymethylprostl 3(trans)-enoate To a solutionof 347 mg. of methyl 9d-hydroxy-l lahydroxymethyll 5-oxoprostl3(trans)-enoate in 20 ml. of ethanol was added 137 mg. of sodium boronhydride in 8 ml. of ethanol under ice cooling and the mixture wasstirred for 1 hour. After completion of the reaction. the reactionmixture was poured into ice-water containing acetic acid and to themixture was added saturated aqueous sodium chloride. The mixture wasextracted with ethyl acetate and the extract was dried over anhydroussodium sulfate. The solvent was distilled off to give 359 mg. of oil.The oil was subjected 5 to column chromatography using 5.0 g. of silicagel and eluted with benzene-ethyl acetate (6:4) to give 156 mg.

of methyl 9a,15B-dihydroxy-l la-hydroxymethylprostl3(trans) -enoate andwith benzene-ethyl acetate (4:6)

to give 127 mg. of methyl 9a,15a-dihydroxy-1lahydroxymethylprost- 1 3trans )enoate. 90:,1Sa-dihydroxy compound IR. (KBr) v max"'": 3300,1741.

N.M.R. (CD COCD A: ppm 5.46 (2H, multiplet,

4.07-3.95 (2H, multiplet,

3.60 (3H, singlet, COOCE 3.50 (2H, multiplet, Cfl Ol-l). 9a,15B-hydroxycompound I.R. (liquid film) 11 max": 3350, 1740.

N.M.R. (CDCl A: ppm, 5.47 (2H, multiplet,

4.10 (2H, mutiplet,

3.80-4.00 (2H, multiplet,

so i. v I

3.87-4.10 (2H, multiplet,

HO H,

3.67 (3H, singlet, COOC I: 3.53 (2H, multiplet, C OH); 2.40 (3H, broadsinglet, 3.0g).

2. 9a (and ,8), ISB-Dihydroxy-l la-hydroxymethylprostl 3(trans)-enoicacid In a mixture of 3.6 ml. of absolute methanol, 0.9 ml. of water and1.5 ml. of 10% aqueous potassium hydroxide was dissolved 124 mg. ofmethyl 901,1 Sa-dihydroxylla-hydroxymethylprost-l3(trans)-enoate and thesolution was stirred for 3 hours at room temperature. The reactionmixture was poured into ice-water containing acetic acid. The mixturewas saturated aqueous sodium chloride and extracted with ethyl acetate.The extract was washed with aqueous saturated sodium chloride and driedover anhydrous sodium sulfate. the solvent was distilled off to give 101mg. of crude crystal. The crystal was recrystallized from ethylacetate-n-hexane to give mg. of9oz,l5a'dihydroxy-1la-hydroxymethylprost-l3(trans)-enoic acid melting at8l82C.

IR. (KBr) v max 3400, 2630, 1710, 1260, 965.

N.M.R. (CD COCD A: ppm 5.45 (2H, multiplet,

4.06 (2H, multiplet,

EXAMPLE6 90 (and 1 B), l Sa-Dihydroxy-l la-hydroxymethyl-'16,l 6-dime-.

thylprost-l3(trans)-enoic acid To a solution of 350 mg. of 9-oi o-llahydroxymethyll Sa-hydroxy-l 6,1 6-dimethylprost' l3(trans)-enoic acidin. ml. of methanol was added 100 mg. of sodium boron hydrideunder icecooling and the mixture was stirred for 30 minutes. After completion ofthe reaction, the reaction mixture was made acidic by addition of aceticacid. The mixture was extracted with ethyl acetate and the solvent wasdistilled off. The residuewas subjected to column chromatography using10 g. of silica gel and eluted with ethyl acetate-benzene 1:1) to give 1mg. of 901,15adihydroxy l la-hydroxymethyll 6, l6-dimethylprostl3(trans)-enoic acid and 95 mg. of 9,8,l5oz-dihydroxy- 1la-hydroxymethyl- 1 6, lY6-dimethylprost-l 3(trans)-v enoic acid. v I 9a( and ,8)-hydroxy compound LR. (CHCI 1 max"" 3240, 2400, 1710, 972.

N.M.R. (CD COCD Azppm, 5.5 (2H, multiplet,

EXAMPLE 7 9a( and B),l5 .-D ihydroxy-l l a-hydroxymethyll 6, 16-dimethylprostl3(trans)-enoic acid sin- To a solution of 295 mg. of,9-oxo-l lahydroxymethybl SB-hydroxy-l 6, 16-dimethylprostl3(trans)enoic acid in 10 ml. of methanol was added 1 l5mg.,of sodium'boron hydride under ice cooling and the mixture wasstirred for minutes. After completion of the reaction, the reactionmixture was treated in the same procedure as in Example 3 to give 85 g.of 9a,15B-dihydroxy-llea-hydroxymethyl-16,16-dimethylprost-l3(trans)-enoic acid and 70 mg. of9,8,15B- dihydroxy-l la-hydroxymethyl- 1 6, l6-dimethylprostl3(trans)-enoic acid.

Using the above procedure, but replacing 9-oxo-l lahydroxymethyllSB-hydroxyl 6, l 6-dimethylprostl3(trans)-enoic acid by methyl9,15-dioxo-l laethoxycarbonyloxymethyll 6, l6-dimethylprostl3(trans)-enoate and 9-hydroxy-l let-hydroxymethyll5-oxol6, l6-dimethylprost-l 3(trans')-enoic acid, there were obtained methyl9,l5-dihydroxy-l laethoxycarbonyl oxymethyll 6, l 6-dimethylprostwhereinA represents an alkylene group having from 4 to 8 carbon atoms, Rrepresents an alkyl group having 0 from 1 to 10 carbon atoms,-Rrepresents hydrogen atom or an alkyl group having from 1 to 6 carbonatoms and R represents'hydrogen atom or an alkoxycarbonyl group havingfrom 1 to 6 carbon atoms in the alkyl moiety and pharmaceuticallyacceptable salts thereof.

2. Compounds having the'formula 2 (CH2) (R 3 R OH C wherein R representsan alkyl group having from 4 to 10 carbon atoms, R represents hydrogenatom or an alkyl group having from 1 to 6 carbon atoms and R representshydrogen atom or an alkoxycarbonyl group having from 1 to 6 carbon atomsin the alkyl moiety and pharmaceutically acceptable salts thereof.

3. 9 a(or B), l5a(or B)-Dihydroxy-llax-hydroxymethylprost-l3(trans)-enoic acid.

4. Methylv 9a(or [3,),15 a(or B)-dihydroxy-llaethoxycarbonyloxymethylprostl 3( trans)-enoate.

5. v 9o (or' B),l5a(or B)-Dihydroxy-l lahydroxymethyll 6, 16-dimethylprostl 3(trans)-enoic acid. i V I i v 6. ,..Methyl 9a(or[3),1501 (or B)-dihydroxy-l lozhydroxymethyi-l 6, l 6-dimethylprostl3(trans)-enoate.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFIQATE OF CORRECTIONPATENT NO. 3 ,899,525 Page 1 of i DATED August 12, 1975 lNVENTOR(5) IOsamu Oda et a1.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Columns 5 and 6 In formulas IX, X, XI and XII, show a dotted line goingfrom the ring structure to the group "R OOCOH C" with the dotted lineattached to the last-mentioned "C" Column 6 In formula XII, show adotted line going from the ring structure to the group "A-COOR with thedotted line attached to "A" Column 8, between lines 40 and 45 delete theformula and rewrite as ---(R P-cH-fi-R Column 10, last line, deleteformula and rewrite as P-CH C-R Column 13, between lines 55 and 60,delete formula and rewrite as

1. COMPOUNDS HAVNG THE FORMULA
 2. Compounds having the formula
 3. 9Alpha (or Beta ), 15 Alpha (or Beta )-Dihydroxy-11 Alpha-hydroxymethylprost-13(trans)-enoic acid.
 4. Methyl 9 Alpha (or Beta),15 Alpha (or Beta )-dihydroxy-11 Alpha-ethoxycarbonyloxymethylprost-13(trans)-enoate.
 5. 9 Alpha (or Beta ),15Alpha (or Beta )-Dihydroxy-11 Alpha-hydroxymethyl-16,16-dimethylprost-13(trans)-enoic acid.
 6. Methyl 9Alpha (or Beta ),15 Alpha (or Beta )-dihydroxy-11 Alpha-hydroxymethyl-16,16-dimethylprost-13(trans)-enoate.